Parenteral Antidepressants: Is America Ready?

Parenteral Antidepressants: Is America Ready?

In spite of the enormous success of antidepressants such as fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft), surprisingly few are available in other than oral form. Although intravenous (IV) clomipramine (Anafranil), imipramine (Tofranil), maprotiline (Ludiomil) and citalopram (Celexa) have been widely used abroad, only amitriptyline (Elavil) is approved and available parenterally in the United States.

The potential advantages of a parenteral route of antidepressant administration include guaranteeing compliance and providing options for patients who cannot tolerate oral medication and an alternative to electroconvulsive therapy for severely ill patients. Pharmacokinetic advantages of parenteral administration include the benefit of greater bioavailability. For IV drugs, bioavailability is 100%, while that of oral drugs is much lower and more variable. For example, studies of oral clomipramine have found bioavailability of roughly 50% (Evans et al., 1980). Parenteral administration circumvents the first-pass liver metabolism, which may both increase plasma levels of the parent compound and reduce metabolite levels. In pharmacokinetic studies of clomipramine, for example, higher serum levels were achieved following intravenous rather than oral administration of the same dose (Evans et al., 1980). Increasing delivery to plasma will increase the delivery to the central nervous system where antidepressants act. Reducing metabolite formation would likely reduce toxicities or adverse events mediated by these compounds. In addition, administering an antidepressant parenterally will accelerate achievement of steady-state drug levels, thereby potentially accelerating therapeutic effect. Finally, it has been suggested that parenteral treatment may have important psychological effects, further medicalizing the treatment procedure and perhaps maximizing therapeutic placebo effect (Adler et al., 1997; Baumann et al., 1998).
Intravenous Antidepressants

Most IV antidepressant drug trials since 1960 have been conducted abroad. Studies have primarily focused on the heterocyclic antidepressants, particularly clomipramine. Of the selective serotonin reuptake inhibitor antidepressants, only citalopram is available intravenously. Problems with the studies done to date include small sample sizes, heterogenous patient diagnoses and populations, lack of control groups, short duration of follow-up, and methodological limitations including open-label design. Nonetheless, studies have generally found intravenous antidepressants to be both effective and well-tolerated.

Clomipramine is the most studied of the IV antidepressants. An initial small open trial found that IV clomipramine given in escalating doses up to 150 mg daily over 21 days was well-tolerated and had a significant, albeit moderate, effect on patients with refractory bipolar depression based on reductions in Hamilton Rating Scale for Depression (HAM-D) scores (Dudley et al., 1980). Other open studies of IV clomipramine reached similar conclusions (Drago et al., 1983; Escobar et al., 1973).

Three clomipramine studies stand out for their double-blind, double-dummy experimental design. Escobar et al. (1973) found no difference in onset of action or improvement of depressive symptoms at 28 days in a placebo-controlled trial comparing oral and IV clomipramine. Their protocol included 10 days using a double-blind, double-dummy placebo-control initial phase (drug infusion given with placebo pill or vice versa), followed by an 18-day open phase in which all 30 patients received oral clomipramine. Two similarly designed studies yielded similar results (Faravelli et al., 1983; Pollock et al., 1989). In the study by Pollock et al. (1989), clomipramine was administered in two pulsed doses (150 mg and 200 mg either oral or IV) 24 hours apart. There was no significant difference in the efficacy or incidence of adverse effects between administration routes, with a 35% reduction in HAM-D scores in all 22 patients studied by day 5. Investigators concluded that the loading-dose regimen produced the rapid effect, not the route of administration. However, an alternative hypothesis would have to consider that all patients knew they were receiving active drug (either IV or oral) and all underwent infusion procedures -- two facts that might inflate placebo response substantially. In a pilot study of pulse dosing of IV clomipramine (75 mg test dose followed by 200 mg 24 hours later) in five adolescents with major depression, Sallee et al. (1989) found a marked decrease in depressive symptoms by HAM-D within the first 36 hours after the infusion, with some return of symptoms by day 7 post-infusion, lending support to the loading-dose hypothesis.

Among studies of other tricyclic antidepressants using double-blind, double-dummy protocols, Deisenhammer et al. (2000) compared high-dose IV amitriptyline (150 mg/day) with medium-dose IV amitriptyline (100 mg/day) and oral amitriptyline (150 mg/day) in a total of 80 patients with major depressive episodes and initial HAM-D scores >18. The initial double-blind phase lasted 14 days, followed by an additional 14 days of open administration of 150 mg/day oral amitriptyline. Investigators found an earlier therapeutic effect in the high-dose IV group according to patients' self-ratings, despite the lack of difference between groups based on the investigators' ratings. More subjects improved (20% reduction in HAM-D scores) in the high-dose IV group than in the other two groups; this difference reached significance at seven days but not at 14 or 28 days. Consistently more subjects responded (50% HAM-D score reduction) in the high-dose IV group compared to the other two groups, although this difference did not attain significance. Improvement in depressive symptoms occurred early; all groups had statistically significant reduction in HAM-D scores by day 2. Investigators concluded that there was no clear advantage to intravenous over oral dosing of amitriptyline and postulated that any differences observed reflected the size of the dose, rather than the route of administration. Limitations in this study included the difficulty controlling for the placebo effect of receiving an infusion and the high drop-out rates that did not differ significantly between groups (56% overall).

Intravenous doxepin (Sinequan) (Adler et al., 1997), trazodone (Desyrel) (Roccatagliata et al., 1977) and imipramine (Crisp, 1966) also have been studied. All were well-tolerated and associated with declines in depressive symptoms. In a randomized, double-blind, double-dummy study, a switch from IV to oral doxepin was done in a step-wise manner over a week such that patients were unaware of when the infusion became placebo (Adler et al., 1997). All patients showed significant improvement in depressive symptoms and no negative effect was observed associated with switching from the IV infusion to oral doxepin, although 30% of subjects had compliance problems with the oral medication. Noting reductions in plasma levels of both doxepin and its metabolite in a subset of patients who worsened with the switch from IV to oral doxepin, investigators concluded that low plasma levels were associated with insufficient response irrespective of dose or route of administration.

Two European, double-blind, double-dummy trials found IV citalopram extremely well-tolerated. The first study involved 60 depressed patients who were given 40 mg/day of either oral or IV citalopram for 10 days followed by a four-week open phase of oral citalopram (Baumann et al., 1998). There was a trend toward a more rapid response (50% reduction in HAM-D-17 scores) in the IV group compared to the oral group at the end of the infusion phase (33% versus 18%). By the end of the four-week oral open phase, the oral-oral group had achieved almost the same response rate as the IV-oral group (66.2% versus 63.3%).

In a larger study by Guelfi et al. (2000), 254 patients with major depression by DSM-IV criteria were randomized to receive citalopram 40 mg/day, either intravenously or orally for the first eight days followed by an open phase of oral medication. The proportion of patients achieving response (50% reduction in Montgomery-Asberg Depression Rating Scale [MADRS] score) by day 42 was significantly greater in the infusion group (77% versus 65%, p=0.037). Similarly, the infusion group demonstrated more improvement on the Clinical Global Impression (CGI) scales at the end of both the infusion phase and the open oral phase. Investigators concluded that there was some benefit of IV over oral delivery, with a significantly better treatment outcome based on MADRS scores and CGI. There was no difference in the emergence of adverse events between the placebo infusion and citalopram infusion groups.
An Alternative Medication

Another research group addressed the delay in onset of antidepressant action associated with traditional agents by studying a naturally produced physiological substance involved in numerous intracellular pathways, S-adenosylmethionine (SAM-e), which may have an antidepressant effect comparable to standard antidepressant agents (Bressa, 1994). Fava et al. (1995) undertook a multicenter open trial of 195 outpatients with DSM-III-R unipolar depressive disorder and treated them with 400 mg/day intramuscular SAM-e for 15 days. The results from the 163 patients who completed the study revealed that mean HAM-D and Patient Global Impression of Severity Scale (PGI-S) scores significantly decreased both at day 7 and day 15 with a significant time effect; 90 patients (55%) were considered to be full responders at day 15. While the investigators were optimistic in considering SAM-e as an agent for improving depressive symptoms, comparison to prior studies of oral SAM-e revealed no difference in rapidity of symptom alleviation between intramuscular and oral administration (Fava et al., 1995).
Transdermal Preparations

The only potential antidepressant under development for transdermal delivery is selegiline (formerly l-deprenyl), an atypical monoamine oxidase inhibitor (MAOI) originally developed as an adjunctive antiparkinsonian drug (Bodkin and Kwon, in press). Currently a selegiline transdermal system (STS) is being investigated for major depression. Unlike oral selegiline, which behaves like a conventional MAOI at doses required for antidepressant efficacy (30 mg to 60 mg), STS does not increase tyramine sensitivity sufficiently to require any dietary restriction (VanDenBerg et al., 2000). The first clinical trial in depression (Bodkin and Amsterdam, 2000) studied 177 patients with major depression at six sites over six weeks and showed the STS (20 mg/day) more effective than placebo after one week of treatment. By the end of six weeks, the STS demonstrated a reduction on the HAM-D-28 of 39% (versus 25% for placebo, p=0.005) and a reduction in MADRS of 34% (19% for placebo, p=0.007). Compared to 28% of the placebo group, 42% of subjects were much or very much improved on the STS. The STS was remarkably well-tolerated, significantly differing in adverse-event profile from placebo in only one symptom: 36% of subjects on STS had local skin irritation, compared to 17% on placebo. Treatment compliance was unusually high, with 89% of subjects on active drug completing the trial and nearly 100% of patches used.
Conclusions

There is a substantial and growing body of research supporting the efficacy and safety of parenterally administered antidepressant drugs, with compelling reasons for their use. To date, only a few studies have demonstrated superiority of parenteral over oral routes of administration in terms of clinical efficacy, but the wide use of IV antidepressant treatment throughout Europe attests to its clinical value as an alternative delivery option. There is now substantial evidence that this route of administration is well tolerated, with no greater incidence of adverse events than oral medication in virtually all comparisons published.

In conclusion, transdermal delivery is a noninvasive and painless route of administration requiring no technical support, which may make parenteral antidepressants more acceptable in this country. Further clinical investigation of its use is certainly warranted.
Acknowledgement

Preparation of this manuscript was supported in part by a NARSAD Young Investigator Award granted to Michael J. Detke, M.D., Ph.D.